HIFU projects: The studies being carried out using high intensity focused ultrasound (HIFU) involve a unique variety of novel applications for drug delivery, cancer therapy, and ablation. Pat efforts for HIFU applications have included uterine fibroid therapies and also clot thrombolysis). Building a foundation for these clinical applications necessitates directed pre-clinical safety and bridging studies that are requisite to bring drug-plus-device paradigms to clinical practice. The optimization of techniques and technologies for uterine fibroid image guided ablation was the first clinical trial for this technology at NIH CC, and was the first USA install of one of the new MRI-guided HIFU technologies that uses MRI temperature maps to localize where the energy is deposited, with a real-time closed loop feedback algorithms that help the physician prescribe and control the energy delivery. This novel technology is also delivered volumetrically and does not require linear sequential rastering, as did the predicate technology. Cavitation detection further improves the safety of this approach. The new clinical HIFU system can apply HIFU very rapidly, which mitigates the excessive time requirements for prior HIFU technologies, which was a major barrier to clinical translation. New tools developed here include programming to enable volumetric hyperthermia and volumetric drug delivery. 1. Enhanced local drug deposition using low temperature sensitive liposomes (LTSLs): In preclinical models, we have shown that local doxorubicin delivery is enhanced in both tumors and muscle by combining systemic injections of LTSLs containing the drug and HIFU exposures. In the tumor studies, enhanced delivery was compared to non-thermo sensitive liposomes and shown to produce improved anti-tumor effects. Low energy HIFU exposures are tailored to generate temperature elevations that are just a few degrees Celsius above body temperature, which are non-destructive, and which cause a phase transition in the liposomes making them more permeable and able to release their payload. The image guided hyperthermia enhances permeability and perfusion as well. A multi-disciplinary approach optimizes these treatments for improving spatial and temporal heating using computer simulations, in vitro experimentation, and in vivo studies. Collaborations with Dieter Haemmerich had developed a multi-parametric mathematical model that combines finite element analysis tools with perfusion modeling, tissue bioheat effects and known drug profiles to try to optimize the drug-plus-device approach prior to translation. Enhanced local drug deposition occurs through non-destructive and destructive mechanisms. Thermal ablation also deposits heat that adds to enhanced permeability and retention as well as mechanical deployment of heat-sensitive nanoparticles. Phase I clinical trials for deposition of chemotherapy with a drug device combination is planned. Preclinical work had focused on development of image-able nanoparticle agents that could theoretically define volumetric drug dosimetry, thus defining tumor at risk for undertreatment. This preclinical drug paintbrush tool had informed past models on the intricate integration of this drug + device combination. Recent efforts have focused on the way that HIFU based actions might potentiate immunotherapies such as check point inhibition. 2. Induced effects for enhancing immunotherapy of tumors: Various studies have shown that HIFU ablation can enhance innate and adaptive immunity against tumors. It is hypothesized that in addition to destroying tumor tissue, tumor associated antigens are being released that can stimulate the immune system to create these effects. With NCI MOB collaborators, we published on the immunogenic effects of radiofrequency thermal ablation, and aim to study further translational opportunities to enhance immunotherapies for cancer. 3. Safety: Studies on the safety and predictability of clinical HIFU exposures with radiology - pathology correlation where possible or correlation with pain control and duration of response. HIFU exposures can produce a variety of effects for both adjunct and stand alone treatments. 4. Cancer applications: Protocols to study HIFU for painful bone metastases as well as MRI-guided HIFU + heat deployed chemotherapy in a nanoparticle liposomal vector delivered IV, and plans are ongoing for clinical translation of HIFU for prostate focal therapy as well as for immunotherapy. Devising a methodology for combining HIFU with other accepted interventional oncology regional and local therapies is a future goal. Image-able liposomes that deploy chemotherapy have been shown in vivo to be able to deposit drug focally with image guidance, like a drug paintbrush. 5. HIFU as a local therapy for prostate cancer has been investigated in animal models here at NIH, and has been translated to clinic by a future CRADA partner. 6. A UO1 grant is ongoing in preclinical models to evaluate HIFU eventually for solid tumors with collaborators at Childrens National Medical Center. This work may be translated to clinic for immune resistant immune cold tumors, in an attempt to convert to hot or immune active tumors.